Angiogenesis is considered as the development of new blood vessels from existing micro-vessels. This process of generating new blood vessels plays an important role in the development of metastases. Under normal physiological conditions, humans or animals suffer angiogenesis in specific and restricted situations, as example in wound healing, in fetal and embryonal development and in the formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system involving angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis.
In tumor angiogenesis, for example, capillary sprouts are formed, their formation being induced by a group of tumor cells. However, compared with blood vessels produced in normal angiogenic microenvironments, tumor micro-vessels are morphologically and functionally unique. Their vascular networks typically show disorganized or aberrant architecture, luminal sizes vary and blood flow can fluctuate chaotically. There are two principal types of tumor angiogenesis in terms of the events which follow implantation of metastatic seedlings on surfaces and in organs. The first or primary angiogenesis is the initial vascularization of the mass of multiplying tumor cells and is regarded as an essential prerequisite for the survival and further growth of a metastatic deposit. The second is a continuing or secondary angiogenesis and is the phenomenon which occurs in waves at the periphery of a growing tumor mass. This second angiogenesis is essential for the accretion of new microcirculatory territories into the service of the expanding and infiltrating tumor.
Angiogenesis is a highly complex process of developing new blood vessels that involves the proliferation and migration of, and tissue infiltration by capillary endothelial cells from pre-existing blood vessels, cell assembly into tubular structures, joining of newly forming tubular assemblies to closed-circuit vascular systems, and maturation of newly formed capillary vessels. The molecular bases of many of these aspects are still not understood.
Angiogenesis is important in normal physiological processes including embryonic development, follicular growth, and wound healing, as well as in pathological conditions such as tumor growth and in non-neoplastic diseases involving abnormal neovascularization, including neovascular glaucoma. Other disease states include but are not limited to, neoplastic diseases, including but not limited to solid tumors, autoimmune diseases and collagen vascular diseases such as, for example, rheumatoid arthritis, and ophthalmological conditions such as diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma. Conditions or diseases to which persistent or uncontrolled angiogenesis contribute have been termed angiogenic dependent or angiogenic associated diseases.
One means of controlling such diseases and pathological conditions comprises restricting the blood supply to those cells involved in mediating or causing the disease or condition. For example, in the case of neoplastic disease, solid tumors develop to a size of about a few millimeters, and further growth is not possible due to absent angiogenesis within the tumor. In the past, strategies to limit the blood supply to tumors have included occluding blood vessels supplying portions of organs in which tumors are present. Such approaches require the site of the tumor to be identified and are generally limited to treatment to a single site, or small number of sites. An additional disadvantage of direct mechanical restriction of a blood supply is that collateral blood vessels develop, often quite rapidly, restoring the blood supply to the tumor. Other approaches have focused on the modulation of factors that are involved in the regulation of angiogenesis. While usually quiescent, vascular endothelial proliferation is highly regulated, even during angiogenesis. Examples of factors that have been implicated as possible regulators of angiogenesis in vivo include, but are not limited to, transforming growth factor beta (TGFβ), acidic and basic fibroblast growth factor (αFGF and (βFGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF).
Brassinosteroids have not been used as anti-angiogenic molecule; brassinosteroids are well-known for antiviral activity and as anti-inflammatory and antiviral agents according the following publications:
European Patent Application EP 2178898 refers to brassinosteroids which having anti-inflammatory and antiviral activity which includes the compounds of formula (I) (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (Compound 1) and (22S,23S)-22,23-dihydroxystigmasta-1,4-dien-3-one (Compound 2).
Publication of Wachsman et al. (Curr. Med. Chem., -Anti-Infective Agents, Antiviral Activity of Natural and Synthetic Brassinosteroids, 2004, Vol. 3, No. 2) refers to the antiviral activity of brassinosteroids which includes the compound (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (Compound 1) included in formula (I) (compound 32b of said publication).